Process for producing β-ketonitrile compound

ABSTRACT

A process comprising reacting an aliphatic carboxylic ester compound with acetonitrile in the presence of a metal alkoxide to yield a metal salt of a β-ketonitrile compound, subsequently transferring the salt to an aqueous medium, and neutralizing the solution to obtain the β-ketonitrile compound in a free state, wherein a water-immisible organic solvent and water are added to the reaction mixture containing the β-ketonitrile compound metal salt yielded to transfer the metal salt to the water, the resultant aqueous solution of the β-ketonitrile compound metal salt is separated from the organic solvent by phase separation or another technique and then neutralized, and the resultant free β-ketonitrile compound is taken out by extraction with an organic solvent.

TECHNICAL FIELD

The present invention relates to a process for producing a β-ketonitrilecompound from an aliphatic carboxylic acid ester compound. Theβ-ketonitrile compound is useful as a starting compound for preparingpharmaceutically active compounds as well as agriculture chemicals.

BACKGROUND ART

As for the process for producing a β-ketonitrile compound by reacting analiphatic carboxylic acid ester compound in the presence of a metalalkoxide, J. Am. Chem. Soc., 56, 1171 (1934) discloses a reactionbetween ethyl isobutylate and acetonitrile in the presence of sodiumethoxide, and Japanese Patent Provisional Publication No. 6-312966discloses a reaction between an acetic acid ester and acetonitile in thepresence of an alkali alcolate.

According to the study performed by the present inventors, it has beenrevealed that the reactions disclosed in the prior art publicationsyield by-products such as 3-oxybutyronitrile and compounds havingpyrimidine nucleus in addition to the desired product of β-ketonitrilecompound. Thus, the known processes could not yield the β-ketonitrilecompound of a high purity in a good yield.

It is an object of the present invention to provide an industriallyapplicable process for producing a β-ketonitrile compound of high purityin a good yield from an easily available aliphatic carboxylic acid estercompound.

DISCLOSURE OF THE INVENTION

The present invention resides in a process for producing a β-ketonitrilecompound having the formula. (3):

in which R¹ represents an aliphatic group which comprises the steps of:

(A) reacting an aliphatic carboxylic acid ester compound having theformula (1):

in which R¹ has the same meaning as defined above, and R² is a groupwhich does not participate in the instant reaction,with acetonitrile in the presence of a metal alkoxide having a metalatom of X to give a reaction mixture containing a metal salt of aβ-ketonitrile compound having the formula (2):

in which R¹ and X have the same meanings as defined above;

(B) adding a water-immiscible organic solvent and water to the reactionmixture, mixing them, and separating the aqueous solution containing themetal salt of β-ketonitrile compound; and

(C) neutralizing the aqueous solution containing the metal salt ofβ-ketonitrile compound by addition of an acid and extracting a freeβ-ketonitrile compound with an organic solvent.

DETAILED DESCRIPTION OF THE INVENTION

The present invention comprises the following three steps:

Step (A): a step of reaction for obtaining a reaction mixture containinga metal salt of a β-ketonitrile compound by reacting an aliphaticcarboxylic acid ester compound and acetonitrile in the presence of ametal alkoxide;

Step (B): a step of separation for obtaining an aqueous solutioncontaining the metal salt of β-ketonitrile compound by mixing thereaction mixture with water and a water-immiscible organic solvent andseparating an aqueous solution from an organic solvent phase;

and

Step (C): a step of neutralization-extraction for obtaining a freeβ-ketonitrile compound by neutralizing the aqueous solution containingthe metal salt of β-ketonitrile compound by addition of an acid and thensubjecting the neutralized mixture to extraction procedure using anorganic solvent.

The above-mentioned three steps are described below in more detail.

(A) Step of Reaction

In this step, an aliphatic carboxylic acid ester compound andacetonitrile are reacted in the presence of a metal alkoxide to preparea metal salt of a β-ketonitrile compound.

The aliphatic carboxylic acid ester compound employed in this step isrepresented by the aforementioned formula (1). In the formula (1), R¹ isan aliphatic group such as an alkyl group, a cycloalkyl group, or anaralkyl group. The alkyl group preferably has 1 to 10 carbon atoms.Examples of the alkyl groups include methyl, ethyl, propyl, butyl,pentyl, hexyl, heptyl, octyl, nonyl, and decyl. These groups may be anyisomers of optionally selected forms. The cycloalkyl group preferablyhas 3 to 7 carbon atoms. Examples of the cycloalkyl groups includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Thesegroups may be any isomers of optionally selected forms. The aralkylgroup preferably has 7 to 10 carbon atoms. Examples of the aralkylgroups include benzyl, phenethyl, phenylpropyl, and phenylbutyl. Thesegroups may be any isomers of optionally selected forms.

In the formula (1), R² is a group which is inert in the reaction andtypically is a hydrocarbyl group. Examples include an alkyl group, acycloalkyl group, an aralkyl group, and an aryl group. The alkyl grouppreferably has 1 to 10 carbon atoms. Examples of the alkyl groupsinclude methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl,nonyl, and decyl. These groups may be any isomers of optionally selectedforms. The cycloalkyl group preferably has 3 to 7 carbon atoms. Examplesof the cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, and cycloheptyl. These groups may be any isomers ofoptionally selected forms. The aralkyl group preferably has 7 to 10carbon atoms. Examples of the aralkyl groups include benzyl, phenethyl,phenylpropyl, and phenylbutyl. These groups may be any isomers ofoptionally selected forms. The aryl group preferably has 6 to 14 carbonatoms. Examples of the aryl groups include phenyl, tolyl, naphthyl, andanthryl. These groups may be any isomers of optionally selected forms.

The metal atom (X) of the metal alkoxide can be an atom of Group IA suchas lithium, sodium, or potassium, an atom of Group 2A such as magnesiumor calcium, or an atom of Group 3B such as aluminum. These Groups aredescribed in Dictionary of Physics and Chemistry, 4th ed. (IwanamiPublishing). Examples of the metal alkoxides include Group 1A metalsalkoxides such as lithium methoxide, sodium methoxide, potassiummethoxide, sodium ethoxide, potassium ethoxide, and potassiumt-butoxide, Group 2A metal alkoxides such as magnesium methoxide andcalcium methoxide, and Group 3B metal alkoxides such as aluminumisopropoxide. Preferred is a sodium alkoxide, and most preferred issodium methoxide.

The metal alkoxide can be employed in an amount of, preferably 1.0 to2.5 moles, more preferably 1.1 to 2.0 moles, per one mole of thealiphatic carboxylic acid ester compound. The metal alkoxides can beemployed singly or in combination of two or more.

Acetonitrile can be employed in the reaction in an amount of, preferably1.1 to 2.5 moles, more preferably 1.2 to 2.0 moles, per one mole of thealiphatic carboxylic acid ester compound.

The reaction is preferably carried out in the presence of not only theacetonitrile (i.e., starting compound which also functions as an organicsolvent) but also a aprotic polar organic solvent. There are no specificlimitations with respect to the aprotic polar organic solvent, so longas it does not participate in the reaction. Preferably, it has arelative dielectric constant (relative permittivity) in the range of 30to 50 at a temperature range of 20 to 25° C. (at an arbitrarytemperature in this range). Examples of these organic solvents includesulfoxides such as dimethyl sulfoxide, sulfones such as sulfolane, ureassuch as N,N′-dimethylimidazolidinone, and amides such asN,N-dimethylacetamide. Preferred are dimethyl sulfoxide andN,N′-dimethylimidazolidinone. The relative dielectric constants aredescribed in “Handbook of Chemistry (II), basic edition, 4th ed.”(Maruzen Publishing), “Solvent Handbook, 1st ed.” (KoudanshaScientific), and “13700 Commercially Available Chemical Products”(Chemical Industry Daily, Ltd.).

The aprotic polar organic solvent can be employed in an amount of,preferably not more than 10 weight parts, more preferably 0.5 to 10weight parts, most preferably 0.75 to 5 weight parts, per one weightpart of the aliphatic carboxylic acid ester compound. These organicsolvents can be used singly or in combination of two or more.

The reaction can be carried out, for instance, under inert gasatmosphere, by mixing a metal alkoxide, an aliphatic carboxylic acidester compound, acetonitrile, and optionally a aprotic polar organicsolvent, and then heating the resulting mixture preferably to 50–110°C., more preferably 60 to 100° C. There is no limitation with respect tothe reaction pressure.

(B) Step of Separation

The step of separation can be carried out by mixing the reaction mixturecontaining β-ketonitrile compound [which was obtained in the step (A)]with water and a water-immiscible organic solvent and subsequentlyseparating an aqueous solution (aqueous phase) containing the metal saltof β-ketonitrile compound from an organic phase by means of, forinstance, phase separation. Examples of the organic solvents includeethers such as diethyl ether and di-isopropyl ether, aromatichydrocarbons such as benzene and toluene, halogenated aromatichydrocarbons such as chlorobenzene and dichlorobenzene, and esters suchas ethyl acetate and butyl acetate. Preferred are ethers and aromatichydrocarbons, and more preferred are aromatic hydrocarbons. Theseorganic solvents can be used singly or in combination of two or more. Ifdesired, a lower alcohol can be added to enhance fluidity, under thecondition that the addition of a lower alcohol does not disturb thephase separation.

The organic solvent is preferably employed in such an amount as to notdisturb the phase separation between the organic phase and aqueousphase. For example, the organic solvent can be used in an amount of,preferably 0.5 to 30 volume parts, more preferably 1 to 10 volume parts,per one part of the aliphatic carboxylic acid ester compound.

Water is used in such an amount as to completely dissolve the resultingmetal salt of β-ketonitrile compound. For example, water can be used inan amount of, preferably 1 to 50 volume parts, more preferably 2 to 30volume parts, per one volume part of the aliphatic carboxylic acid estercompound.

The step of phase separation is preferably carried out by first addingthe organic solvent to the reaction liquid (reaction mixture) so as toenhance fluidity and then adding water under stirring. In thisprocedure, the reaction liquid is preferably kept at a temperature inthe range of 10 to 50° C., more preferably 20 to 40° C. This procedureis favorably adopted for keeping the reaction liquid fromsolidification.

(C) Step of Neutralization-Extraction

The step of neutralization-extraction is carried out for adding an acidto the aqueous solution containing a metal salt of β-ketonitrilecompound (which was obtained in the step of separation) forneutralization and then extracting the resulting free β-ketonitrilecompound with an organic solvent. Examples of the acids employable inthis step include hydrochloric acid, sulfuric acid, nitric acid,phosphoric acid, methanesulfonic acid, acetic acid, and ammoniumchloride (or aqueous ammonium chloride). Preferred are hydrochloricacid, sulfuric acid, and ammonium chloride (or aqueous ammoniumchloride). The acid can be added in such an amount as to make pH of theaqueous solution to preferably 6–10. It is desired that the addition ofacid is carried out to keep the temperature of the aqueous solution at0–50° C.

There are no specific limitations with respect to the organic solventemployed in the step of neutralization-extraction, so long as it canextract the free β-ketonitrile compound from the aqueous solution. Theorganic solvent preferably is immiscible with water. Examples of theorganic solvents include aromatic hydrocarbons such as benzene andtoluene, esters. such as ethyl acetate and butyl acetate, andhalogenated hydrocarbons such as dichloromethane and dichloroethane.Preferred are aromatic hydrocarbons and acetic acid esters. Morepreferred are aromatic hydrocarbons.

The organic solvent can be employed in such an amount as to extract thefree β-ketonitrile compound produced in the aqueous solution byneutralization.

By the step of neutralization-extraction, a free β-ketonitrile compoundis obtained with a high purity in the form of an organic solventsolution. The resulting product or solution can be further subjected toconventional after-treatment procedures such as concentration,distillation, crystallization, recrystallization, or columnchromatography. It should be noted that the β-ketonitrile compound isunstable on heating. Therefore, when the distillation is carried out, athin layer distillation apparatus or a flow-down film distillationapparatus is preferably employed.

The present invention is further described by the following non-limitingexamples.

EXAMPLE 1 Preparation of 3-cyclopropyl-3-oxopropio-nitrile

In a glass flask (inner volume: 1,000 mL) equipped with a stirrer, athermometer, a dropping funnel and a reflux condenser were placed 81.0 g(1.5 mol) of sodium methoxide, 100.0 g (1.0 mol) of methylcyclopropanecarboxylate and 61.5 g (1.5 mol) of acetonitrile undernitrogen atmosphere. The mixture was heated under reflux at 82° C. for 6hours. After the reaction was complete, 400 mL of toluene was added tothe reaction mixture, and the resulting mixture was cooled to roomtemperature. To the cooled mixture was dropwise added 200 mL of waterunder stirring, keeping the temperature of the mixture at 30° C. orlower. Thus produced aqueous portion was taken out.

Subsequently, to the aqueous portion was added 135 mL (1.6 mol) ofhydrochloric acid (12 mol/L), while chilling the aqueous portion in anice bath. After the aqueous solution became to have pH 7.0, the solutionwas subjected to extraction using three portions of 200 mL toluene. Thetoluene portions were combined and washed with 50 mL of an aqueoussaturated sodium hydrogen carbonate solution and then dried overmagnesium sulfate. The toluene solution was filtered and then analyzedby high performance liquid chromatography (absolute quantitativeanalysis). It was confirmed that the following products were produced:

-   -   3-cyclopropyl-3-oxopropionitrile (desired product):        -   81.1 g (yield: 74%)    -   3-oxobutyronitrile (by-product):        -   0.45 g (0.55 wt. % of the desired product)    -   Compound having pyrimidine nucleus (by-product):        -   0.15 g (0.18 wt. % of the desired product).

The filtered toluene solution was concentrated under reduced pressure togive 80.2 g (isolation yield: 72%) of 3-cyclopropyl-3-oxopropionitrile(purity: 98.2%) as yellow liquid. The purity was determined by highperformance liquid chromatography.

The obtained 3-cyclopropyl-3-oxopropionitrile had the followingcharacteristics:

EI-MS (m/e) : 69 (M-CH₂CN), CI-MS (m/e): 110 (M+1)

IR (cm⁻¹, liquid film): 3200–2900, 2261, 1713, 1389, 1073, 953

¹H-NMR (CDCl₃, δ(ppm)): 1.05–1.15 (2H, m), 1.18–1.25 (2H, m), 2.06–2.15(1H, m), 3.64 (2H, s).

REFERENCE EXAMPLE 1 Preparation of 3-cyclopropyl-3-oxopropionitrile(with No Phase Separation Step)

In the reaction apparatus described in Example 1 were placed 81.0 g (1.5mol) of sodium methoxide, 100.0 g (1.0 mol) of methylcyclopropanecarboxylate and 61.5 g (1.5 mol) of acetonitrile undernitrogen atmosphere. The mixture was heated under reflux at 82° C. for 6hours. After the reaction was complete, 400 mL of toluene was added tothe reaction mixture, and the resulting mixture was cooled to roomtemperature. To the cooled mixture were added 280 mL (1.7 mol) ofhydrochloric acid (6 mol/L) and 100 mL of water, keeping the temperatureof the resulting mixture at 30° C. or lower. After the reaction mixturebecame to have pH 2.0, the mixture was extracted with 3 portions of 200mL toluene. The toluene portions were combined and washed with 50 mL ofan aqueous saturated sodium hydrogen carbonate solution and then driedover magnesium sulfate. The toluene solution was filtered and thenanalyzed by high performance liquid chromatography (absolutequantitative analysis). It was confirmed that the following productswere produced:

-   -   3-cyclopropyl-3-oxopropionitrile (desired product):        -   72.3 g (yield: 66%)    -   3-oxobutyronitrile (by-product):        -   0.60 g (0.83 wt. % of the desired product)    -   Compound having pyrimidine nucleus (by-product):        -   1.33 g (1.8 wt. % of the desired product).

The filtered toluene solution was concentrated under reduced pressure togive 77.2 g (isolation yield: 66%) of 3-cyclopropyl-3-oxopropionitrile(purity: 93.6%) as yellow liquid. The purity was determined by highperformance liquid chromatography.

EXAMPLE 2 Preparation of 4-methyl-3-oxopentanenitrile

In the reaction apparatus described in Example 1 were placed 81.0 g (1.5mol) of sodium methoxide, 102.1 g (1.0 mol) of methyl isobutylate, and61.5 g (1.5 mol) of acetonitrile under nitrogen atmosphere. The mixturewas. heated under reflux at 82° C. for 6 hours. After the reaction wascomplete, 400 mL of toluene was added to the reaction mixture, and theresulting mixture was cooled to room temperature. To the cooled mixturewas dropwise added 200 mL of water under stirring, keeping thetemperature of the mixture at 35° C. or lower. Thus produced aqueousportion was taken out.

Subsequently, to the aqueous portion was added 95 mL (1.1 mol) ofhydrochloric acid (12 mol/L), while chilling the aqueous portion in anice bath. After the aqueous solution became to have pH 7.7, the solutionwas subjected to extraction using three portions of 300 mL toluene. Thetoluene portions were combined and washed with 50 mL of an aqueoussaturated sodium hydrogen carbonate solution and then dried overmagnesium sulfate. The toluene solution was filtered and concentratedunder reduced pressure to give 78.9 g (isolation yield: 70%) of4-methyl-3-oxopentanenitrile (purity: 98.5%, according to areapercentage determined by high performance liquid chromatography) as paleyellow liquid.

The obtained 4-methyl-3-oxopentanenitrile had the followingcharacteristics:

EI-MS (m/e): 71 (M-CH₂CN), CI-MS (m/e): 112 (M+1)

IR (cm⁻¹, liquid film): 3700–3100, 3100–2800, 2263, 1725, 1468, 1389,1306, 1048, 939

¹H-NMR (CDCl₃, δ(ppm)): 1.18 (6H, d, J=6.8 Hz), 2.84 (1H, m), 3.94 (2H,s).

EXAMPLE 3 Preparation of 4,4-dimethyl-3-oxopentane-nitrile

In a glass flask (inner volume: 100 mL) equipped with a stirrer, athermometer, a dropping funnel and a reflux condenser were placed 8.10 g(0.15 mol) of sodium methoxide, 11.62 g (0.1 mol) of methyl pivalate,and 6.15 g (0.15 mol) of acetonitrile under nitrogen atmosphere. Themixture was heated under reflux at 82° C. for 6 hours. After thereaction was complete, 40 mL of toluene was added to the reactionmixture, and the resulting mixture was cooled to room temperature. Tothe cooled mixture was dropwise added 45 mL of water under stirring,keeping the temperature of the mixture at 35° C. or lower. Thus producedaqueous portion was taken out.

Subsequently, to the aqueous portion was added 9.5 mL (0.11 mol) ofhydrochloric acid (12 mol/L), while chilling the aqueous portion in anice bath. After the aqueous solution became to have pH 7.7, the solutionwas subjected to extraction using three portions of 30 mL toluene. Thetoluene portions were combined and washed with 50 mL of an aqueoussaturated sodium hydrogen carbonate solution and then dried overmagnesium sulfate. The toluene solution was filtered and then analyzedby high performance liquid chromatography (absolute quantitativeanalysis). It was confirmed that the following products were produced:

-   -   4,4-dimethyl-3-oxopentanenitrile (desired product):        -   7.25 g (yield: 58%)    -   3-oxobutyronitrile (by-product):        -   0.01 g (0.20 wt. % of the desired product)    -   Compound having pyrimidine nucleus (by-product):        -   0.01 g (0.14 wt. % of the desired product).

The filtered toluene solution was concentrated under reduced pressure togive 7.21 g (isolation yield: 57%) of 4,4-dimethyl-3-oxopentanenitrile(purity: 98.4%, according to area percentage determined by highperformance liquid chromatography) as pale yellow solid.

The obtained 4,4-dimethyl-3-oxopentanenitrile had the followingcharacteristics:

EI-MS (m/e): 57 (M-COCH₂CN), CI-MS (m/e): 126 (M+1)

IR (cm⁻¹, liquid film): 3000–2800, 2266, 1721, 1485, 1391, 1325, 1067,935

¹H-NMR (CDCl₃, δ(ppm)): 1.21 (9H, s), 3.70 (2H, s)

m.p.: 67.8–68.7° C.

REFERENCE EXAMPLE 2 Preparation of 4,4-dimethyl-3-oxopentanenitrile(with No Phase Separation Step)

In the reaction apparatus described in Example 3 were placed 8.10 g(0.15 mol) of sodium methoxide, 11.62 g (0.10 mol) of methyl pivalate,and 6.15 g (0.15 mol) of acetonitrile under nitrogen atmosphere. Themixture was heated under reflux at 82° C. for 6 hours. After thereaction was complete, 40 mL of toluene was added to the reactionmixture, and the resulting mixture was cooled to room temperature. Tothe cooled mixture were added 28 mL (0.17 mol) of hydrochloric acid (6mol/L) and 10 mL of water, keeping the temperature of the resultingmixture at 30° C. or lower. After the reaction mixture became to have pH2.0, the mixture was extracted with 3 portions of 20 mL toluene. Thetoluene portions were combined and washed with 50 mL of an aqueoussaturated sodium hydrogen carbonate solution and then dried overmagnesium sulfate. The toluene solution was filtered and then analyzedby high performance liquid chromatography (absolute quantitativeanalysis). It was confirmed that the following products were produced:

-   -   4,4-dimethyl-3-oxopentanenitrile (desired product):        -   7.22 g (yield: 58%)    -   3-oxobutyronitrile (by-product):        -   0.04 g (0.55 wt. % of the desired product)    -   Compound having pyrimidine nucleus (by-product):        -   0.13 g (1.8 wt. % of the desired product).

The filtered toluene solution was concentrated under reduced pressure togive 7.63 g (isolation yield: 58%) of 4,4-dimethyl-3-oxopentanenitrile(purity: 94.6%, according to area percentage determined by highperformance liquid chromatography) as pale yellow liquid.

EXAMPLE 4 Preparation of 3-cyclopropyl-3-oxopropio-nitrile

In a glass flask (inner volume: 500 mL) equipped with a stirrer, athermometer, a dropping funnel and a reflux condenser were placed 40.5 g(0.75 mol) of sodium methoxide, 50.0 g (0.50 mol) of methylcyclopropanecarboxylate, 30.8 g (0.75 mol) of acetonitrile, and 50 g ofdimethyl sulfoxide (relative dielectric constant at 20° C.: 48.9) undernitrogen atmosphere. The mixture was heated under reflux at 82° C. for 6hours. After the reaction was complete, the reaction mixture wasanalyzed by high performance liquid chromatography (absolutequantitative analysis). It was confirmed that the following productswere produced:

-   -   3-cyclopropyl-3-oxopropionitrile (desired product):        -   47.5 g (yield: 87%)    -   3-oxobutyronitrile (by-product):        -   0.65 g (1.4 wt. % of the desired product)    -   Compound having pyrimidine nucleus (by-product):        -   0.36 g (0.76 wt. % of the desired product).

Subsequently, 400 mL of toluene was added to the reaction mixture. Tothe mixture was dropwise added 100 mL of water under stirring, keepingthe temperature of the mixture at 30° C. or lower. Thus produced aqueousportion was taken out.

Subsequently, to the aqueous portion was added 70 mL (0.84 mol) ofhydrochloric acid (12 mol/L), while chilling the aqueous portion in anice bath. After the aqueous solution became to have pH 7.0, the solutionwas subjected to extraction using three portions of 100 mL toluene. Thetoluene portions were combined and washed with 30 mL of an aqueoussaturated sodium hydrogen carbonate solution and then dried overmagnesium sulfate. The toluene solution was filtered and then analyzedby high performance liquid chromatography (absolute quantitativeanalysis). It was confirmed that the following products were produced:

-   -   3-cyclopropyl-3-oxopropionitrile (desired product):        -   45.4 g (yield: 83%)    -   3-oxobutyronitrile (by-product):        -   0.15 g (0.33 wt. % of the desired product)    -   Compound having pyrimidine nucleus (by-product):        -   0.04 g (0.09 wt. % of the desired product).

EXAMPLE 5 Preparation of 3-cyclopropyl-3-oxopropio-nitrile

The procedures of Example 4 were repeated except that dimethyl sulfoxide(aprotic polar organic solvent) was replaced withN,N′-dimethylimidazolidinone (relative dielectric constant at 25° C.:37.6). The reaction was carried out in the manner as described inExample 1.

After the reaction was complete, the reaction mixture was analyzed byhigh performance liquid chromatography (absolute quantitative analysis).It was confirmed that the following products were produced:

-   -   3-cyclopropyl-3-oxopropionitrile (desired product):        -   47.2 g (yield: 87%)    -   3-oxobutyronitrile (by-product):        -   0.53 g (1.1 wt. % of the desired product)    -   Compound having pyrimidine nucleus (by-product):        -   0.60 g (1.3 wt. % of the desired product).

Subsequently, the step of phase separation and step ofneutralization-extraction were carried out in the manner as described inExample 1. After these steps were complete, the reaction mixture wasanalyzed by high performance liquid chromatography (absolutequantitative analysis). It was confirmed that the following productswere produced:

-   -   3-cyclopropyl-3-oxopropionitrile (desired product):        -   45.3 g (yield: 83%)    -   3-oxobutyronitrile (by-product):        -   0.04 g (0.09 wt. % of the desired product)    -   Compound having pyrimidine nucleus (by-product):        -   0.15 g (0.33 wt. % of the desired product).

REFERENCE EXAMPLE 3 Preparation of 3-cyclopropyl-3-oxopropionitrile(with No Phase Separation Step)

In the reaction apparatus described in Example 4 were placed 40.5 g(0.75 mol) of sodium methoxide, 50.0 g (0.50 mol) of methylcyclopropanecarboxylate, 30.8 g (0.75 mol) of acetonitrile, and 50 g ofdimethyl sulfoxide (relative dielectric constant at 20° C.: 48.9) undernitrogen atmosphere. The mixture was heated under reflux at 82° C. for 6hours. After the reaction was complete, the reaction mixture wasanalyzed by high performance liquid chromatography (absolutequantitative analysis). It was confirmed that the following productswere produced:

-   -   3-cyclopropyl-3-oxopropionitrile (desired product):        -   47.1 g (yield: 86%)    -   3-oxobutyronitrile (by-product):        -   0.44 g (0.93 wt. % of the desired product)    -   Compound having pyrimidine nucleus (by-product):        -   0.41 g (0.87 wt. % of the desired product).

Subsequently, 400 mL of toluene was added to the reaction mixture. Tothe mixture were added 56.7 mL (0.68 mol) of hydrochloric acid (12mol/L) and 100 mL of water, keeping the temperature of the mixture at30° C. or lower. After the aqueous solution became to have pH 2.0, thesolution was subjected to extraction using three portions of 100 mLtoluene. The toluene portions were combined and washed with 30 mL of anaqueous saturated sodium hydrogen carbonate solution and then dried overmagnesium sulfate. The toluene solution was filtered and analyzed byhigh performance liquid chromatography (absolute quantitative analysis).It was confirmed that the following products were produced:

-   -   3-cyclopropyl-3-oxopropionitrile (desired product):        -   44.2 g (yield: 81%)    -   3-oxobutyronitrile (by-product):        -   0.16 g (0.36 wt. % of the desired product)    -   Compound having pyrimidine nucleus (by-product):        -   0.40 g (0.90 wt. % of the desired product).

EXAMPLE 6 Preparation of 4-methyl-3-oxopentanenitrile

In the reaction apparatus described in Example 4 were placed 40.5 g(0.75 mol) of sodium methoxide, 51.1 g (0.50 mol) of methyl isobutylate,30.8 g (0.75 mol) of acetonitrile, and 51 g of dimethyl sulfoxide(relative dielectric constant at 20° C.: 48.9) under nitrogenatmosphere. The mixture was heated under reflux at 82° C. for 6 hours.After the reaction was complete, the resulting mixture was cooled toroom temperature. The cooled reaction mixture was analyzed by highperformance liquid chromatography (absolute quantitative analysis). Itwas confirmed that the following products were produced:

-   -   4-methyl-3-oxopentanenitrile (desired product):        -   46.1 g (yield: 83%)    -   3-oxobutyronitrile (by-product):        -   0.23 g (0.50 wt. % of the desired product)    -   Compound having pyrimidine nucleus (by-product):        -   0.41 g (0.89 wt. % of the desired product).

Subsequently, 100 mL of toluene was added to the reaction mixture, andthe mixture was cooled to room temperature. To the mixture was dropwiseadded 100 mL of water under stirring, keeping the temperature of themixture at 30° C. or lower. Thus produced aqueous portion was taken out.

Subsequently, to the aqueous portion was added 56.5 mL (0.68 mol) ofhydrochloric acid (12 mol/L), while chilling the aqueous portion in anice bath. After the aqueous solution became to have pH 7.0, the solutionwas subjected to extraction using three portions of 100 mL toluene. Thetoluene portions were combined and washed with 30 mL of an aqueoussaturated sodium hydrogen carbonate solution and then dried overmagnesium sulfate. The toluene solution was filtered and then analyzedby high performance liquid chromatography (absolute quantitativeanalysis). It was confirmed that the following products were produced:

-   -   4-methyl-3-oxopentanenitrile (desired product):        -   43.9 g (yield: 79%)    -   3-oxobutyronitrile (by-product):        -   0.14 g (0.32 wt. % of the desired product)    -   Compound having pyrimidine nucleus (by-product):        -   0.06 g (0.14 wt. % of the desired product).

EXAMPLE 7 Preparation of 4,4-dimethyl-3-oxopentane-nitrile

In a glass flask (inner volume: 100 mL) equipped with a stirrer, athermometer, a dropping funnel and a reflux condenser were placed 8.10 g(0.15 mol) of sodium methoxide, 11.62 g (0.1 mol) of methyl pivalate,6.15 g (0.15 mol) of acetonitrile, and 11.62 g of dimethyl sulfoxide(relative dielectric constant at 20° C.: 48.9) under nitrogenatmosphere. The mixture was heated under reflux at 82° C. for 6 hours.After the reaction was complete, 23 mL of toluene was added to thereaction mixture, and the resulting mixture was cooled to roomtemperature. To the cooled mixture was dropwise added 23 mL of waterunder stirring, keeping the temperature of the mixture at 30° C. orlower. Thus produced aqueous portion was taken out.

Subsequently, to the aqueous portion was added 14 mL (0.17 mol) ofhydrochloric acid (12 mol/L), while chilling the aqueous portion in anice bath. After the aqueous solution became to have pH 7.0, the solutionwas subjected to extraction using three portions of 30 mL toluene. Thetoluene portions were combined and washed with 30 mL of an aqueoussaturated sodium hydrogen carbonate solution and then dried overmagnesium sulfate. The toluene solution was filtered and then analyzedby high performance liquid chromatography (absolute quantitativeanalysis). It was confirmed that the following products were produced:

-   -   4,4-dimethyl-3-oxopentanenitrile (desired product):        -   9.76 g (yield: 78%)    -   3-oxobutyronitrile (by-product):        -   0.03 g (0.31 wt. % of the desired product)    -   Compound having pyrimidine nucleus (by-product):        -   0.01 g (0.10 wt. % of the desired product).

REFERENCE EXAMPLE 4 Preparation of 4,4-dimethyl-3-oxopentanenitrile(with No Phase Separation Step)

In the reaction apparatus described in Example 4 were placed 40.5 g(0.75 mol) of sodium methoxide, 58.1 g (0.50 mol) of methyl pivalate,30.8 g (0.75 mol) of acetonitrile, and 58.1 g of dimethyl sulfoxide(relative dielectric constant at 20° C.: 48.9) under nitrogenatmosphere. The mixture was heated under reflux at 82° C. for 6 hours.After the reaction was complete, 400 mL of toluene was added to thereaction mixture. To the mixture were added 56.7 mL (0.68 mol) ofhydrochloric acid (12 mol/L) and 100 mL of water, keeping thetemperature of the resulting mixture at 30° C. or lower. After thereaction mixture became to have pH 2.0, the mixture was extracted with 3portions of 100 mL toluene. The toluene portions were combined andwashed with 30 mL of an aqueous saturated sodium hydrogen carbonatesolution and then dried over magnesium sulfate. The toluene solution wasfiltered and then analyzed by high performance liquid chromatography(absolute quantitative analysis). It was confirmed that the followingproducts were produced:

-   -   4,4-dimethyl-3-oxopentanenitrile (desired product):        -   48.7 g (yield: 78%)    -   3-oxobutyronitrile (by-product):        -   0.20 g (0.42 wt. % of the desired product)    -   Compound having pyrimidine nucleus (by-product):        -   0.28 g (0.57 wt. % of the desired product).

EXAMPLE 8 Preparation of 3-oxopentanenitrile

In the reaction apparatus described in Example 7 were placed 8.10 g(0.15 mol) of sodium methoxide, 8.81 g (0.10 mol) of methyl propionate,6.15 g (0.15 mol) of acetonitrile, and 11.62 g of dimethyl sulfoxide(relative dielectric constant at 20° C.: 48.9) under nitrogenatmosphere. The mixture was heated under reflux at 82° C. for 6 hours.After the reaction was complete, to the resulting mixture was added 20mL of toluene, and the mixture was cooled to room temperature. To themixture were dropwise added 20 mL of water under stirring, keeping thetemperature of the resulting mixture at 30° C. or lower. The aqueousportion was then taken out.

To the aqueous portion was added 14 mL (0.17 mol) of hydrochloric acid(12 mol/L), while chilling the aqueous portion in an ice bath. After theaqueous solution became to have pH 7.0, the solution was subjected toextraction using three portions of 20 mL toluene. The toluene portionswere combined and washed with 30 mL of an aqueous saturated sodiumhydrogen carbonate solution and then dried over magnesium sulfate. Thetoluene solution was filtered and then analyzed by high performanceliquid chromatography (absolute quantitative analysis). It was confirmedthat the following products were produced

-   -   3-oxopentanenitrile (desired product):        -   6.11 g (yield: 63%)    -   3-oxobutyronitrile (by-product):        -   0.03 g (0.49 wt. % of the desired product)    -   Compound having pyrimidine nucleus (by-product):        -   0.01 g (0.16 wt. % of the desired product).

EXAMPLE 9 Preparation of 4-phenyl-3-oxobutyronitrile

In the reaction apparatus described in Example 7 were placed 8.10 g(0.15 mol) of sodium methoxide, 15.02 g (0.10 mol) of methylphenylacetate, 6.15 g (0.15 mol) of acetonitrile, and 15.02 g ofdimethyl sulfoxide (relative electric constant at 20° C.: 48.9) undernitrogen atmosphere. The mixture was heated under reflux at 82° C. for 4hours. After the reaction was complete, to the resulting mixture wasadded 30 mL of toluene, and the mixture was cooled to room temperature.To the mixture were dropwise added 50 mL of water under stirring,keeping the temperature of the resulting mixture at 30° C. or lower. Theaqueous portion was then taken out.

To the aqueous portion was added 14 mL (0.17 mol) of hydrochloric acid(12 mol/L), while chilling the aqueous portion in an ice bath. After theaqueous solution became to have pH 7.0, the solution was subjected toextraction using three portions of 30 mL toluene. The toluene portionswere combined and washed with 30 mL of an aqueous saturated sodiumhydrogen carbonate solution and then dried over magnesium sulfate. Thetoluene solution was filtered and then analyzed by high performanceliquid chromatography (absolute quantitative analysis). It was confirmedthat the following products were produced:

-   -   4-phenyl-3-oxobutyronitrile (desired product):        -   11.11 g (yield: 70%)    -   3-oxobutyronitrile (by-product):        -   0.03 g (0.27 wt. % of the desired product)    -   Compound having pyrimidine nucleus (by-product):        -   0.01 g (0.09 wt. % of the desired product).

INDUSTRIAL APPLICABILITY

By utilizing the present invention, a β-ketonitrile compound of a highpurity can be obtained in a high yield and with simple procedures froman easily available aliphatic carboxylic acid ester compound andacetonitrile.

1. A process for producing a β-ketonitrile compound having the formula(3):

in which R¹ represents an aliphatic group which comprises the steps of:(A) reacting an aliphatic carboxylic acid ester compound having theformula (1):

in which R¹ has the same meaning as above, and R² is a hydrocarbylgroup, with acetonitrile in the presence of a metal alkoxide having ametal atom of X to give a reaction mixture containing a metal salt of aβ-ketonitrile compound having the formula (2):

in which R¹ and X have the same meanings as above; (B) adding awater-immiscible organic solvent and water to the reaction mixture,mixing them, and separating the aqueous solution containing the metalsalt of β-ketonitrile compound; and (C) neutralizing the aqueoussolution containing the metal salt of β-ketonitrile compound by additionof an acid and extracting a free β-ketonitrile compound with an organicsolvent.
 2. The process of claim 1, wherein the step of reacting analiphatic carboxylic acid ester compound and acetonitrile in thepresence of a metal alkoxide is performed in the presence of a aproticpolar organic solvent.
 3. The process of claim 2, wherein the aproticpolar organic solvent is an organic solvent having a relative dielectricconstant in the range of 30 to 50 at a temperature range of 20 to 25° C.4. The process of claim 3, wherein the aprotic polar organic solventhaving a relative dielectric constant in the range of 30 to 50 at atemperature range of 20 to 25° C. is dimethyl sulfoxide orN,N′-dimethyl-imidazolidinone.
 5. The process of claim 1, wherein theacetonitrile is employed in an amount of 1.1 to 2.5 moles per one moleof the aliphatic carboxylic acid ester compound.
 6. The process of claim1, wherein the step of reacting an aliphatic carboxylic acid estercompound and acetonitrile in the presence of a metal alkoxide isperformed at a temperature in the range of 50 to 110° C.
 7. The processof claim 1, wherein the separating step (B) comprises procedures ofadding to the reaction mixture the water-immiscible organic solvent andwater and then stirring the resulting mixture with addition of water. 8.The process of claim 1, wherein the neutralization of the step (C) isperformed by adding an acid to the aqueous solution containing the metalsalt of β-ketonitrile compound to give an aqueous solution of pH 6 to10.